Orexin

Orexin (/ɒˈrɛksɪn/), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, in which the sufferer experiences brief losses of muscle tone (cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it. Orexin (/ɒˈrɛksɪn/), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, in which the sufferer experiences brief losses of muscle tone (cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it. There are only 10,000–20,000 orexin-producing neurons in the human brain, located predominantly in the perifornical area and lateral hypothalamus. They project widely throughout the central nervous system, regulating wakefulness, feeding, and other behaviours. There are two types of orexin peptide and two types of orexin receptor. Orexin was discovered in 1998 almost simultaneously by two independent groups of researchers working on the rat brain. One group named it orexin, from orexis, meaning 'appetite' in Greek; the other group named it hypocretin, because it is produced in the hypothalamus and bears a weak resemblance to secretin, another peptide. The use of both terms is now a practical necessity, as hypocretin is used to refer to the genetic products and orexin is used to refer to the protein products. There is a high affinity between the orexin system in the rat brain and that in the human brain. In 1998, reports of the discovery of orexin/hypocretin were published nearly simultaneously. Luis de Lecea, Thomas Kilduff, and colleagues reported the discovery of the hypocretin system at the same time as Takeshi Sakurai from Masashi Yanagisawa's lab at the University of Texas Southwestern Medical Center at Dallas reported the discovery of the orexins to reflect the orexigenic (appetite-stimulating) activity of these peptides. In their 1998 paper describing these neuropeptides, they also reported discovery of two orexin receptors, dubbed OX1R and OX2R. The two groups also took different approaches towards their discovery. One team was interested in finding new genes that were expressed in the hypothalamus. In 1996, scientists from the Scripps Research Institute reported the discovery of several genes in the rat brain, including one they dubbed 'clone 35.' Their work showed that clone 35 expression was limited to the lateral hypothalamus. They extracted selective DNA found in the lateral hypothalamus. They cloned this DNA and studied it using electron microscopy. Neurotransmitters found in this area were oddly similar to the gut hormone, secretin, a member of the incretin family, so they named hypocretin to stand for a hypothalamic member of the incretin family. These cells were first thought to reside and work only within the lateral hypothalamus area, but immunocytochemistry tactics revealed the various projections this area truly had to other parts of the brain. A majority of these projections reached the limbic system and structures associated with it (including the amygdala, septum, and basal forebrain area). On the other hand, Sakurai and colleagues were studying the orexin system as orphan receptors. To this end, they used transgenic cell lines that expressed individual orphan receptors and then exposed them to different potential ligands. They found that the orexin peptides activated the cells expressing the orexin receptors and went on to find orexin peptide expression specifically in the hypothalamus. Additionally, when either orexin peptide was administered to rats it stimulated feeding, giving rise to the name 'orexin'. The nomenclature of the orexin/hypocretin system now recognizes the history of its discovery. 'Hypocretin' refers to the gene or genetic products and 'orexin' refers to the protein, reflecting the differing approaches that resulted in its discovery. The use of both terms is also a practical necessity because 'HCRT' is the standard gene symbol in databases like GenBank and 'OX' is used to refer to the pharmacology of the peptide system by the International Union of Basic and Clinical Pharmacology. There are two types of orexin: orexin-A and -B (hypocretin-1 and -2). They are excitatory neuropeptides with approximately 50% sequence identity, produced by cleavage of a single precursor protein. Orexin-A is 33 amino acid residues long and has two intrachain disulfide bonds; orexin-B is a linear 28 amino acid residue peptide. Although these peptides are produced by a very small population of cells in the lateral and posterior hypothalamus, they send projections throughout the brain. The orexin peptides bind to the two G-protein coupled orexin receptors, OX1 and OX2, with orexin-A binding to both OX1 and OX2 with approximately equal affinity while orexin-B binds mainly to OX2 and is 5 times less potent at OX1. The orexins are strongly conserved peptides, found in all major classes of vertebrates.